WELCOME to the homepage for HENRY M. SOBELL
[Article on Acinomycin in World Journal for Pharmaceutical Research, 2017]
[Article: How Actinomycin Binds to DNA, Atlas of Science, 2017]
[HMS lecture] at the [Weizmann Institute], June 2015.
[Book 1: Premeltons in DNA]
[Book 2: Organization of DNA in Chromatin]
[PREMELTONS IN DNA -- Review Article appearing in JSFG, March 2016]
Henry M. Sobell is internationally renowned for his pioneering contributions to the understanding of how the anticancer agent, actinomycin D, binds to DNA and exerts its mechanism of action. Using the technique of X-ray crystallography, he and his research colleague, Shri C. Jain, solved the structure of a crystalline complex containing actinomycin and deoxyguanosine, and the information obtained from their study led them to propose a model to understand the general features of how actinomycin binds to DNA.
According to this model, the phenoxazone ring system on actinomycin intercalates between adjacent base pairs, while pentapeptide chains lie in the narrow groove of the B- helix and form hydrogen bonds (in the case of d (pGpC) sequences) with guanine residues on opposite chains. X-ray crystallographic studies of actinomycin complexed to a number of different self-complementary oligonucleotides have now confirmed the overall features of this model. However, the precise nature of the DNA conformation remains unknown due to problems inherent in refining large structures with limited resolution data. Implicit in the original model was the assumption that actinomycin binds to B-DNA or to a distorted form of B-DNA. The possibility that actinomycin might bind to some other discretely different DNA conformational state was not envisioned at that time.
[See "How Actinomycin Binds to DNA"]
Together with his research team, Dr. Sobell continued to extend his crystallographic studies to include other intercalators (these contain a diverse variety of heterocyclic ring systems) complexed to a number of different self-complementary DNA and RNA dinucleotides. The information obtained from these studies led him to propose the existence of beta-DNA, a metastable and hyperflexible DNA form (a form very different from the Watson-Crick B- and A- structures), which, he believes, is intimately associated with the intercalation process. The existence of this beta-DNA structure required modification to the original actinomycin-DNA binding model. When combined with the realization that beta-DNA is an obligatory structural intermediate (i.e., transition state intermediate) in the unwinding of duplex DNA leading to melting, this novel beta-DNA binding model leads to understanding the mechanism of action of actinomycin.
[See "Actinomycin and DNA Transcription"]
The importance of beta-DNA as a key premelted DNA form led Dr. Sobell and his research colleague, Asok Banerjee to further postulate that collectively localized nonlinear excitations (solitons) exist in DNA structure. These arise as a consequence of an intrinsic nonlinear instability associated with interconversions between the two predominant sugar-pucker conformations, C2' endo and C3' endo, that accompany base-pair unstacking. In their bound state, soliton-antisoliton pairs surround small beta-DNA core regions - these regions undergo breathing motions that can facilitate the intercalation of drugs and dyes into DNA. Such bound state structures can, in addition, nucleate DNA melting and give rise to other types of DNA phase transitions. They have been called "premeltons".
[See "Presence of Nonlinear Excitations in DNA Structure and their relationship to DNA Premelting and to Drug Intercalation"]
This website has been created for physicists and biologists to deepen their understanding of the structure and physical properties of DNA. It has also been created for younger students, those majoring in physics, applied mathematics, physical chemistry and molecular biology. Senior undergraduates in physics and in applied mathematics, as well as first year graduate students in these areas, should have little difficulty in understanding the basic physical concepts presented here. However, to acquire an overall perspective in molecular biology, additional courses in chemistry and in biochemistry are strongly recommended. Likewise, graduate students in molecular biology and in physical chemistry should expand their graduate curriculum to include more advanced physics and applied mathematics courses. This will assist them in understanding the relevant advances in nonlinear mathematics that have taken place over the past twenty-five years.
Henry M. Sobell was born in Los Angeles, California November 7, 1935, and grew up in Brooklyn, New York, where he attended Brooklyn Technical High School (1948-1952), Columbia College (1952-1956) and the University of Virginia School of Medicine (1956-1960). Instead of practicing clinical medicine, Dr. Sobell then went to the Massachusetts Institute of Technology, Cambridge, Massachusetts, to join Professor Alexander Rich in the Department of Biology (1960-1965) where, as a Helen Hay Whitney Postdoctoral Fellow, he learned the technique of single-crystal X-ray analysis. Dr. Sobell joined the Chemistry Department at the University of Rochester, College of Arts and Sciences, and was then jointly appointed to the Department of Biophysics at the University of Rochester School of Medicine and Dentistry, becoming a full professor in both departments (1965-1993). He is now retired and living in the Adirondacks in Lake Luzerne, New York.
I owe a debt of gratitude to my research colleagues whose efforts have led to the creation of this website: A. Banerjee, K.K. Bhandary, S.C. Jain, E.D. Lozansky, B.S. Reddy, T.D. Sakore, T.P. Seshadri and C. -C. Tsai.
I also thank Alwyn Scott and James Krumhansl for scientific discussions, Tom O'Brien for devising the animations that appear in this website, Stanley Goldberg for editing the text, and Leah Goldberg and Marc Peterson for their patience and skill in creating this website.
Finally, I wish to express my appreciation to Dr. Robin Motz, a close personal friend over the years. Dr. Motz is a physician who practices internal medicine in the New York City area. Earlier, he was professor of physics at Stevens Institute of Technology, specializing in plasma physics. His unusual background [Ph.D., Physics, Columbia University, 1965; M.D., Columbia University College of Physicians and Surgeons, 1975] allowed him to read this website critically and to contribute valuable discussion.
Modified, December 25, 2015
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